1. Field of the Invention
This invention relates to histamine H.sub.2 -receptor antagonists and more particularly to those antagonists having a tropane ring joining an imidazole-like ring to a thiourea group.
2. Description of the Prior Art
The pharmacological actions of histamine are mediated by at least two distinct classes of receptors. One receptor type, designated H.sub.1, mediates histamine-induced contraction of smooth muscle of the small intestine and bronchi. A second receptor type, designated H.sub.2, mediates the action of histamine in vivo stimulating gastric acid secretion and in vitro inhibiting contractions of the rat uterus and increasing the rate of beating of the guinea pig atrium. The receptors in these and other tissues are defined pharmacologically from the antagonists shown below, which selectively block the responses of the tissues to histamine stimulation. ##STR2##
A clear distinction between the structural features of the H.sub.1 -antagonists and the H.sub.2 -antagonists is evident. The H.sub.1 -antagonists have aryl or heteroaryl rings that need not have any structural relationship to the imidazole ring of histamine, but possess a side chain which is positively charged at physiological pH. The aryl rings perhaps act in hydrophobic binding to the H.sub.1 -receptor and are also responsible for the inherent lipophilicity in these compounds (partition coefficient, P=2500 for diphenhydramine). Because of this liophilicity, H.sub.1 -antagonists are significantly distributed to the central nervous system. The H.sub.2 -antagonists resemble histamine in having an imidazole or similar unsaturated, heterocyclic ring but have an uncharged, though polar, side chain. These compounds are hydrophilic (P=2.5 for cimetidine) and like histamine (P=0.2) do not cross the blood-brain-barrier in appreciable concentrations. These substantial differences probably account for the considerable selectivity shown by the respective antagonists in distinguishing the two types of receptors. Thus, it is assumed that H.sub.1 -receptor recognition is determined primarily by the ammonium group, while at H.sub.2 -receptors, affinity is determined by the imidazole or imidazole-like ring.
Heterocyclic ring variation of H.sub.2 -antagonists has usually involved other nitrogen containing aromatic rings such as thiazole and pyridine. Recently the prototype of a new class of H.sub.2 -antagonists structurally characterized by a furan ring system has been introduced. Ranitidine, shown below, was found to be a competitive antagonist, more potent than cimetidine ##STR3## in the guinea pig isolated right atrium and in preventing histamine-induced gastric acid secretion in dogs. Thus an imidazole ring does not appear to be an essential recognition factor for the H.sub.2 -receptor, although structural similarity needs to be retained.
The first orally effective H.sub.2 -receptor antagonist to be developed was metiamide, whose structure has been previously given above. In clinical trials, metiamide was found to be effective in promoting the healing of peptic ulcers. However, metiamide was found to produce agranulocytosis through suppression of the cell-cycle of precursors of white blood cells. This effect has since been attributed to the thiourea moiety, since agranulocytosis was also encountered with the use of thioamide compounds to treat hyperthyroidism. This problem was overcome when the methylthiourea moiety was replaced with a methylnitriloguanidine moiety to give cimetidine.
Cimetidine was found to be a satisfactory replacement for metiamide, being initially a potent H.sub.2 -antagonist and, after extensive clinical trials, generally a safe agent for the treatment of peptic ulcer and associated gastrointestinal disorders. However, there have been a number of reports of various side effects, and, as experience with the drug mounts, newer adverse reactions are being reported in increasing frequency.
Accordingly, there exists a need for new and different H.sub.2 -receptor antagonists of demonstrated efficacy.